While cervical and other genital cancers are primarily caused by Human Papilloma Virus (HPV) infections, recent studies have demonstrated that HPV is also associated with head and neck (HN) cancers. The prevalence of oral HPV infection among men and women aged 14 to 69 years in the US is about 7%, however, 90% of University of Michigan (UM) oropharyngeal squamous cancer (OPSC) patients carry high-risk HPV. Indeed, the incidence of HPV- associated OPSCs is increasing and OPSC has become the most common HPV-related cancer in the US. HPV has been shown to disrupt several key cancer pathways in oropharyngeal squamous cell lines, including p53 and Rb, but many open questions remain regarding oral HPV transmission epidemiology, infection and persistence, the mechanisms of HPV HN carcinogenesis, and the connection between the ongoing oral HPV epidemic and the rising OPSC incidence. The overarching goal of this proposal is to understand the mechanistic effects of HPV infection on the regulatory pathways of oropharyngeal carcinogenesis, and how these effects in turn shape the observed age-specific incidence and mortality of OPSCs. This problem is inherently multi-scale, as population level HPV transmission drives dynamic, ongoing changes to intracellular cancer regulatory pathways, which in turn drives population-level trends in cancer incidence and mortality. Thus, understanding the rising incidence in OPSC necessitates tying together both the population level processes of infectious disease and the population-level cancer incidence through the mechanistic interactions between HPV and carcinogenesis. Toward this goal, we will develop systems biology models of the main proliferation regulatory networks affected by HPV, and assess the consequences of HPV infection, integration and alternate transcripts on the dynamics of HPV-positive tumor cell proliferation. We will integrate these mechanistic infection and cancer models into multistage models of carcinogenesis to gauge the impacts of HPV infection on the population-level age-specific incidence and mortality of OPSC. We will use these integrated multiscale cancer models in combination with population-level oral HPV transmission models to predict the effects of current HPV prevalence trends on future rates of OPSCs and the potential impact of vaccination and other prevention strategies. Our systems models will be based on multiscale inference using mechanistic infection and cancer data.